Administration of therapeutic peptides requires peptide formulations that remain stable during storage. In general, parenteral administration is used with peptides because of their increased size and subsequent difficulty in crossing biological membranes. Peptides can be particularly difficult to formulate because of their tendency to degrade over time and/or undergo aggregation and precipitation. Degradation, aggregation, and precipitation are all indicative of an unstable formulation. Such an unstable formulation is not commercially viable, as it cannot pass U.S. Food and Drug Administration approval.
Formulation variables which affect the degradation of peptides during storage include, but are not limited to, pH, the quantity of salts present, and the type and quantity of excipients. In addition, temperatures, pressures, and time for freezing and drying cycles can affect the stability of a lyophilized peptide formulation. The role of most of these variables has been studied; however, the synergistic effect of the variables is still poorly understood.
Glucagon-like peptide-2 (GLP-2) is a 33 amino acid peptide having therapeutic applications in the treatment of diseases of the gastrointestinal tract. In particular, it has been determined that GLP-2 and analogs thereof act as trophic agents to enhance and maintain the functioning of the gastrointestinal tract and to promote growth of intestinal tissue. See e.g., U.S. Pat. Nos. 5,834,428; 5,789,379; and 5,990,077; and International Publication No. WO 98/52600.
Commercial exploitation of GLP-2 or an analog thereof requires a stable GLP-2 formulation that can be readily prepared using a commercially acceptable process. Because GLP-2 is a protein, and thus far more labile than traditional small molecular weight drugs, the formulation of GLP-2 or an analog thereof presents challenges not commonly encountered by the pharmaceutical industry. For example, methionine oxidation at position 10 and aspargine deamination at position 11, 16, and/or 24 of GLP-2 are potential routes of degradation. Furthermore, GLP-2 or an analog thereof may also be adsorbed to surfaces to form aggregates and/or precipitate, which would then render the formulation unstable.
There is a need in the art for stable formulations of GLP-2 peptides and analogs thereof which can be prepared using a commercially acceptable process. The present invention satisfies these needs.